Targeted delivery of DNA for gene therapy via receptors

The general concept of targeted delivery of therapeutic agents was first recognized by Paul Ehrlich at the turn of the century I. Only recently has this strategy been applied to the delivery of DNA-protein complexes to cells 2. Most of the research on D N A delivery by this approach has been performed by targeting the liver-specific asialoglycoprotein receptor (ASGPr) (Refs 3-10) and the relatively ubiquitous transferrin receptor,1 19. DNA delivery to hepatocytes has also been effected using insulin-polylysine conjugates 2°, and to antigen-bearing cells using an antibody 21. The majority of these experiments use a covalently crosslinked receptor ligand-polycation conjugate to bind DNA in an electrostatic complex 5 (Fig. 1). Receptormediated endocytosis of the ligand carries the bound DNA into a cell, allowing subsequent expression of the foreign DNA (Fig. 2). This technique, which has been demonstrated in animals using the ASGPr (Refs 5-8), is promising for the delivery of therapeutic DNAs as well as antisense oligonucleotides2L